Background

Klippel-Trenaunay-Weber syndrome (KTWS) is characterized by a triad of port-wine stain, varicose veins, and bony and soft tissue hypertrophy involving an extremity. Note the image below.

Klippel-Trenaunay syndrome in a young person. Note the port-wine stain extending to the buttocks. These lesions can be associated with venous malformations involving the rectum and bladder.

In 1900, noted French physicians Klippel and Trenaunay first described a syndrome in 2 patients presenting with a port-wine stain and varicosities of an extremity associated with hypertrophy of the affected limb's bony and soft tissue. They termed the syndrome "naevus vasculosus osteohypertrophicus." In 1907, Parkes Weber, unaware of Klippel and Trenaunay's report, described a patient with the 3 aforementioned symptoms as well as an arteriovenous malformation of the affected extremity. He termed the process hemangiectatic hypertrophy.

Today, conflicting opinion exists in the literature as whether to separately designate the original triad as Klippel-Trenaunay syndrome and the triad with the addition of arteriovenous malformation as Parkes Weber syndrome. Making the distinction is probably wise given the increased morbidity associated with arteriovenous malformations. For this discussion, the 2 types are considered together.

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Pathophysiology

The exact cause of Klippel-Trenaunay-Weber syndrome (KTWS) remains to be elucidated, although several theories exist. Bliznak and Staple suggested intrauterine damage to the sympathetic ganglia or intermediolateral tract leading to dilated microscopic arteriovenous anastomoses as the cause.
[1] Servelle believes that deep vein abnormalities, with resultant obstruction of venous flow, lead to venous hypertension, the development of varices, and limb hypertrophy.
[2] Baskerville et al contend that a mesodermal defect during fetal development causes maintenance of microscopic arteriovenous communications.
[3] Finally, McGrory and Amadio believe that an underlying mixed mesodermal and ectodermal dysplasia is likely responsible for the development of KTWS.
[4]

Most cases KTWS are sporadic, although a few cases in the literature report an autosomal dominant pattern of inheritance.
[5] A case report of KTWS in a monozygotic twin with an unaffected twin advances the theory of a paradominant inheritance pattern.
[6] This theory suggests that KTWS is produced by a single gene defect lethal in individuals who are homozygous for this gene. Heterozygotes carry the gene but are unaffected. The disease manifests in individuals who demonstrate loss of heterozygosity from a somatic mutation during embryogenesis. In these individuals, only the skin region harboring this cell population demonstrates the KTWS mutation.

The association between the angiogenic factor gene AGGF1 and KTS appears to be significant.
[7] Common AGGF1 variants may confer risk of KTWS.

Kihiczak et al report that KTWS may result from a pathogenic gene for vascular and tissue overgrowth.
[8]